The chronic fatigue syndrome (CFS) is a common disorder of unknown cause that incapacitates young individuals in their most productive years. There is evidence that orthostatic intolerance may play a role in the fatigue of patients with CFS. The broad long-term objectives of the project are to delineate the pathophysiology and pathogenesis of orthostatic intolerance in the chronic fatigue syndrome (CFS); to investigate the role of orthostatic intolerance in producing the symptoms of CFS; to use this information to institute physiologically appropriate therapeutic interventions; and thereby decrease the symptoms of fatigue. The Specific Aims of the application are to enhance cardiovagal outflow with low dose atropine and Iosartan and examine the cardiovascular response to orthostatic stress; to characterizing sympathetic nervous transduction to vascular resistance in the lower limbs and characterize the sympathetic responses in the lower limbs to orthostatic stress; to measure transcapillary interstitial fluid filtration during orthostatic stress determine the relationship between capillary filtration and plasma volume; and characterize cerebral blood flow, systemic pressure maintenance, postural tachycardia and parasympathetic outflow. We will assess arterial baroreflex gain by measuring the heart rate and muscle sympathetic nerve activity response to pharmacological provocations; sympathetic transduction by relating muscle sympathetic nerve activity to peripheral resistance; plasma volume using the Evans Blue dye method; venous compliance using venous occlusion plethysmography; and cerebral blood flow velocity with transcranial Doppler. These measures, which comprise the elements of orthostatic tolerance, will be compared with healthy controls selected to match the gender, age and level of physical activity of the subjects. The relationships between these variables and role of covariates such as the level of physical activity and psychiatric state, determined with standardized instruments, will be analyzed using multivariate statistics.